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1.
Neuroscience ; 293: 67-79, 2015 May 07.
Article in English | MEDLINE | ID: mdl-25748530

ABSTRACT

Aversive experiences in early life are thought to dispose to psychopathologies such as mood or anxiety disorders. In a two-hit stress model, we assessed the effects of juvenile and/or adult stress on the 5-HT-mediated modulation of synaptic inhibition of ventral dentate gyrus granule cells. Combined but not single stress exposure led to a significant reduction in activity and increased anxiety-like behavior. Similarly, the 5-HT1A receptor-mediated inhibition of evoked inhibitory postsynaptic currents (IPSCs) of granule cells was only reduced in single stress exposed animals. This was also true for the number of granule cells responding with a 5-HT3 receptor-dependent burst of miniature IPSCs. 5-HT3 receptors are expressed on cholecystokinin (CCK)+ basket cells in the hippocampus. In fact, we observed a reduction of steady-state mRNA levels of CCK+ basket cell markers after single juvenile or adult stress and partial recovery after combined stress, thus matching the electrophysiological findings. Adaptive changes in 5-HT-mediated modulation of synaptic inhibition and CCK+ basket cells in the DG may help to maintain normal levels of anxiety after single juvenile or adult stress exposure, as indicated by the increased anxiety that accompanies the loss of this regulation upon combined stress.


Subject(s)
Dentate Gyrus/physiopathology , Neurons/physiology , Receptor, Serotonin, 5-HT1A/physiology , Receptors, Serotonin, 5-HT3/physiology , Stress, Psychological/physiopathology , Age Factors , Animals , Anxiety/physiopathology , Dentate Gyrus/drug effects , Inhibitory Postsynaptic Potentials/drug effects , Interneurons/metabolism , Male , Neural Inhibition/drug effects , Neurons/drug effects , Rats , Receptor, Serotonin, 5-HT1A/metabolism , Receptors, Serotonin, 5-HT3/metabolism , Serotonin/administration & dosage , Serotonin Receptor Agonists/administration & dosage , gamma-Aminobutyric Acid/metabolism
2.
Neuroscience ; 286: 325-37, 2015 Feb 12.
Article in English | MEDLINE | ID: mdl-25498224

ABSTRACT

Norepinephrine acting via ß-adrenergic receptors (ß-ARs) plays an important role in hippocampal plasticity including the subiculum which is the principal target of CA1 pyramidal cells and which controls information transfer from the hippocampus to other brain regions including the neighboring presubiculum and the entorhinal cortex (EC). Subicular pyramidal cells are classified as regular- (RS) and burst-spiking (BS) cells. Activation of ß-ARs at CA1-subiculum synapses induces long-term potentiation (LTP) in burst- but not in RS cells (Wójtowicz et al., 2010). To elucidate seizure-associated disturbances in the norepinephrine-dependent modulation of hippocampal output, we investigated the functional consequences of the ß-AR-dependent synaptic plasticity at CA1-subiculum synapses for the transfer of hippocampal output to the parahippocampal region in the pilocarpine model of temporal lobe epilepsy. Using single-cell and multi-channel field recordings in slices, we studied ß-AR-mediated changes in the functional connectivity between CA1, the subiculum and its target-structures. We confirm that application of the ß-adrenergic agonist isoproterenol induces LTP in subicular BS- but not RS cells. Due to the distinct spatial distribution of RS- and BS cells in the proximo-to-distal axis of the subiculum, in field recordings, LTP was significantly stronger in the distal than in the proximal subiculum. In pilocarpine-treated animals, ß-AR-mediated LTP was strongly reduced in the distal subiculum. The attenuated LTP was associated with a disturbed polysynaptic transmission from the CA1, via the subiculum to the presubiculum, but with a preserved transmission to the medial EC. Our findings suggest that synaptic plasticity may influence target-related information flow and that such regulation is disturbed in pilocarpine-treated epileptic rats.


Subject(s)
Epilepsy, Temporal Lobe/physiopathology , Hippocampus/physiopathology , Pyramidal Cells/physiopathology , Receptors, Adrenergic, beta/physiology , Action Potentials/drug effects , Adrenergic beta-Agonists/pharmacology , Animals , Disease Models, Animal , Electric Stimulation , Epilepsy, Temporal Lobe/chemically induced , Hippocampus/drug effects , Isoproterenol/pharmacology , Long-Term Potentiation , Male , Parahippocampal Gyrus/drug effects , Parahippocampal Gyrus/physiopathology , Pilocarpine , Pyramidal Cells/drug effects , Rats , Rats, Wistar
3.
Neuropharmacology ; 53(3): 415-20, 2007 Sep.
Article in English | MEDLINE | ID: mdl-17632186

ABSTRACT

Memantine is an uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist which is registered in both Europe and the USA for the treatment of Alzheimer's disease (AD). Cultured rat hippocampal neurons were used to evaluate the potency and blocking kinetics of this therapeutically very well-tolerated agent in the presence of various concentrations of the synthetic agonist NMDA and a constant, saturating concentration of the co-agonist D-serine (10 microM). Whole-cell patch-clamp experiments at -70 mV revealed that the degree of "equilibrium" blockade of NMDA-induced currents by memantine was largely unaffected by the concentration of the agonist NMDA. The IC50 values for NMDA at 300, 100, 30 and 10 microM were 0.80+/-0.12, 1.01+/-0.08, 0.92+/-0.13 and 1.31+/-0.09 microM, respectively, giving an average IC(50) for all agonists concentrations tested of 1.01+/-0.11 microM. In contrast, and as expected, the onset and offset kinetics of blockade were clearly dependent on agonist concentration. For NMDA 300, 100, 30 and 10 microM, kon values were 10.55+/-1.41, 8.60+/-0.17, 4.90+/-0.20 and 3.22+/-0.08x10(4) M(-1) s(-1), respectively; 1/tauon values at the IC50 concentration of memantine-i.e. 1 microM-were 0.58+/-0.11, 0.28+/-0.05, 0.15+/-0.02 and 0.11+/-0.03 s(-1), respectively and koff values were 0.24+/-0.01, 0.19+/-0.01, 0.14+/-0.00 and 0.09+/-0.01 s(-1), respectively. It therefore appears that the kinetics, but not the equilibrium potency, of memantine are agonist concentration-dependent. These fast agonist concentration-dependent kinetic properties, in addition to the clear voltage-dependence of memantine, are proposed to be important for the therapeutic tolerability of this compound in the treatment of AD.


Subject(s)
Excitatory Amino Acid Antagonists/pharmacology , Memantine/pharmacology , N-Methylaspartate/pharmacology , Neurons/drug effects , Receptors, N-Methyl-D-Aspartate/agonists , Animals , Cells, Cultured , Dose-Response Relationship, Drug , Dose-Response Relationship, Radiation , Drug Interactions , Electric Stimulation/methods , Embryo, Mammalian , Hippocampus/cytology , Kinetics , Membrane Potentials/drug effects , Membrane Potentials/physiology , Membrane Potentials/radiation effects , Patch-Clamp Techniques , Rats
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